Project Summary/Abstract Understanding how the human brain produces cognition ultimately depends on precise quantitative characterization of context-dependent dynamic functional networks (DFN) that transiently link distributed brain regions. Progress in achieving this goal has been limited due to a lack of theoretical frameworks for characterizing DFNs and appropriate computational methods to test them. Devising and validating computational methods for investigating DFNs in the human brain is thus of great significance. The first major goal of this proposal is to address a critical need in human brain research by developing novel algorithms for identifying DFNs and characterizing dynamic network interactions between distributed brain regions. To achieve this goal, we will develop and validate novel computational methods within the framework of Bayesian switching linear dynamical systems (BSDS) with vector autoregressive models (VAR) and factor analysis (FA) that overcome major limitations of existing methods for investigating dynamic interactions in the human brain. The second major goal of this proposal is to use BSDS to investigate DFNs underlying cognitive function in healthy adults, and in patients with Parkinson's disease (PD). Severe cognitive impairment is one of the most devastating behavioral outcomes in patients with PD, yet little is known about the temporal properties of dysfunctional neurocognitive systems in this debilitating disorder. The computational algorithms we propose to develop, validate, and apply will allow us to rigorously investigate brain dynamics that support critical cognitive functions and significantly advance our understanding of dynamic processes underlying human brain function and dysfunction. Our proposed studies will also, for the first time, investigate DFNs in simulated, rodent in vivo optogenetic fMRI, as well as human data using state-of-the-art (sub- second) high-temporal resolution fMRI data generated by the NIH-funded Stanford Alzheimer's Disease Research Center (ADRC), highlighting critical translational applications of our proposed methods. Our proposed studies will provide novel tools for investigating dynamic functional networks in the human brain, with innovative applications to the Human Connectome Project (HCP) and the study of neurological disorders and clinical neuroscience more broadly. The proposed studies are highly relevant to the mission of the BRAIN Initiative (RFA-EB-15-006), which calls for the development and dissemination of innovative computational tools for probing human brain function and dysfunction. Our computational tools will be widely disseminated to facilitate research into the dynamical aspects of human brain function.